Saliva is an essential oral lubricant containing an array of vital proteins for maintaining oral health. Head and neck cancers account for 3% of all malignancies in the United States. Dry mouth due to significant decreases in saliva secretion (xerostomia) is a permanent and devastating side effect of head and neck radiation that affects approximately 40,000 patients a year in the U.S. Radiation treatment (RT) preferentially damages secretory acinar cells, resulting in a near-complete loss of saliva, a dramatic increase in tooth decay, difficulty in swallowing, and other issues. Radiation treatment in patients with head and neck tumors commonly results in hyposalivation and xerostomia due to the loss of fluid secreting salivary acinar cells. Patients develop susceptibility to oral infections, dental caries, impaired speech and swallowing, reducing the quality of life.
Clinical management is largely unsatisfactory. Current prevention methods (e.g. radioprotective agents or highly localized intensity modulated RT) are generally ineffective. Although advanced radiation techniques such as Intensity-Modulated Radiation Therapy (IMRT) significantly reduce radiation to the salivary glands compared to conventional radiation, a large percentage of patients develop xerostomia post-IMRT. Post-radiotherapy palliative therapies remain largely ineffective for long-term resolution of xerostomia. Other xerostomia treatments, such as artificial saliva or stimulatory agonists, are also largely ineffective. Tissue engineering offers a potential safe clinical solution for the regeneration of tissue and recovery of salivary function.
Recent clinical success in tissue engineering includes tissues such as cartilage, bone and bladder. U.S. Pat. Nos. 7,803,905 and 7,875,591, the entireties of which are hereby incorporated by reference, discuss methods of adhering cells to scaffolds and devices to induce replication of connective tissues. Functional reconstitution of a 3D glandular structure such as the human salivary gland is difficult, owing to a complex tissue structure of distinct cell types that must reassemble to provide vectorial secretion of a complex biological fluid. Despite extensive recent research in salivary gland development, efforts at regeneration using the classic tissue engineering models are few, and suffer from insufficient sources of cells and scaffold materials. Synthetic scaffolds, such as PGA/PLLA lack necessary cues, have inappropriate mechanical properties, and produce potentially inflammatory degradation byproducts. Collagen/matrigel hybrids are closer matches to native tissue, both in gel modulus and composition, but murine Matrigel cannot be used for human repair. Recent work suggests that well-defined polysaccharide gels may be a potential solution. Cell sourcing remains a substantial obstacle, with researchers reporting difficulties in reliably isolating and expanding human acinar, ductal, and myoepithelial cells (MECs).